In typical solid phase chromatography processes, a solution containing a mixture of substances is passed through a bed of adsorbent. One or more of the dissolved substances in the flow has a greater tendency to be adsorbed onto the solid matrix than others. In the case of gel filtration separation is based on molecular weight, with small substances permeating the gel which retards their movement through the gel relative to larger molecules which are excluded from the pores of the gel. In ion exchange chromatography, the principle of separation involves differential interaction with a resin of different molecules according to their charge properties. The resins may consist of a backbone polymer to which selected functional chemical groups are appended. Ionic interactions cause some molecules to bind to the resin, while others pass through the resin bed. Over the years, a large variety of resins and other chromatographic substrates have become commercially available.
Small scale laboratory solid chromatography is generally carried out in a column or cartridge. The column comprises a hollow cylinder with fittings at both ends, the bottom end of the cylinder containing a frit with pores of smaller size than the gel or resin particles to retain the solid substrate in the column. A slurry is poured into the column and the substrate is packed by eluting solution through the column. When a sample containing a mixture of molecules to be separated is applied to the appropriate resin bed, a molecule to be separated binds to the resin, and the unbound components travel through the column and out at the bottom. A desorbent is then eluted which releases the bound molecule, and it too passes through the column. Typically in a laboratory small aliquots of eluted liquid are collected in an automatic fraction collector. Since the column is now filled with desorbent, it must be washed with a starting buffer to regenerate the functional groups on the resin before another sample batch can be applied.
In the laboratory, the batch type chromatography process is satisfactory because many applications are analytical. Even when preparative quantities are recovered, the amounts needed are relatively small, and sufficient reagent is obtainable by one or a few batch runs. However, batch type chromatography is generally unsuitable for large industrial purifications. The time consumed by washing and regeneration of columns is not cost effective. Also, many writers have pointed out that in a batch system, only a fraction of the resin bed is actually in use in each cycle, resulting in production inefficiencies. See U.S. Pat. No. 5,156,736 and U.S. Pat. No. 4,379,751. Finally, batch processes are wasteful of reagents whose only function is to wash and regenerate the column.
Over forty years ago, a new process was developed specifically for large scale industrial purifications. U.S. Pat. No. 2,985,589 disclosed a chromatography system involving a separation tower divided into a number of individual separation beds. These beds are connected in series, and the outlet at the bottom most bed is connected to a pump that retuned flow in a continuous loop to the upper most bed. The inlet apparatus for each bed has a port connected to a downward flowing conduit. The conduits terminate in fittings attached to a rotary valve designed to control both ingress and egress of liquids into or from the inlets to each individual bed. The system is called Simulated Moving Bed (SMB) chromatography because the beds appear to be moving in a direction countercurrent to the direction of flow.
FIG. 1 is a schematic depicting the principle of SMB chromatography. The figure shows eight individual chromatography columns arranged in series bottom to top in a continuous loop. A pump is represented by an oval at the left. Also, two inlets marked D and F are shown, as well as two outlets E and R. F stands for feed, and it is at this point fresh feedstock containing the mixture of substances to be separated is added to the system. D denotes the desorbent inlet. At this point the solution is added containing an agent releasing species of molecule which was previously bound to the solid substrate. R stands for raffinate, the term given to the flow from the system containing all of the molecular species which did not bind to the column, and E is the exit line carrying away previously bound species, released by the desorbate.
FIG. 2 is a graphical representation materials status of distribution at one point in time. The graph defines four zones according to the predominant function occurring in twelve columns. In this illustration, there are six columns in the series. In zone I, bound species are eluted from the solid substrates by infusion of eluent at a point where the level of unbound species is minimal. Zones II and III. At the point of greatest separation, the raffinate is drawn off, thereby eliminating the unbound species at a point where most of the species with affinity for the solid matrix is already bound. Finally this diagram shows Zone IV, which provides for recycling of eluent. The most common applications involve some type of affinity resin, but SMB can be utilized in molecular weight differentiating subjects as well, as disclosed in U.S. Pat. No. 6,551,512.
Referring again to FIG. 1, in the diagram, feedstock is shown entering column 6, raffinate is removed prior to entry of flow into column 8, desorbent is added to the stream prior to entry of flow to column 2, and extract is removed before entry of flow to column 4. In the next step, however, the inlets and outlets are shifted one position counterclockwise to positions 5, 7, 1, and 3; and so on in successive steps. Thus, there is a substantially continuous inflow of feedstock, and a simultaneous collection of purified extract.
The continuous nature of SMB operation is characterized by very brief flow stoppages during the port switchovers in successive process steps. However, since all input and output conduits briefly stop at the same time, there are no significant pressure drops or surges in the system. Indexing of mechanical rotors is designed to effect rapid switchovers, even on very large industrial machines. Further, strategy in the design of process configuration is largely dictated by the affinity and release characteristics of bound species to the solid substrate, exclusion properties of unbound species, the bed volume required to obtain separation of by-product, and other factors. Where separations involve more than two components, the use of coupled SMB systems may be advantageous, as demonstrated in U.S. Pat. Nos. 6,379,554 and 6,662,420. In the case of the '554 patent, the desired product is removed in the raffinate of the first SMB loop, and further purified in a second loop to separate high molecular compounds, ash content, etc. See also U.S. Pat. No. 6,402,959. A similar system is disclosed in U.S. Pat. No. 5,122,275 in which two interconnected SMB trains of columns alternate, resulting in reduced processing time compared to a single train having twice as many columns.
In over forty years since the '589 patent issued, there have been over 200 patents issued on modifications of SMB disclosing improvements in separation efficiency generally, or in particular applications, enhanced purity and yield in the final products, or reduction in required volume desorbent. For example, in one variation disclosed in U.S. Pat. No. 5,156,736, separations are performed in a single bed preserving the principles of SMB by interposing at various levels in the bed a series of crossectionally functional collecting and distribution means for adding feedstock and recycled process liquid, collecting raffinate, distributing eluent, and recovering extract product. Equilibrium is established in the system by very precise flow and pressure control. In U.S. Pat. No. 5,595,665, flushing apparatus is provided generally comprising a fluid distribution manifold, whereby incoming line fluid will enter an equalization chamber and be removed by a connecting conduit. Contamination by trailing peaks is thereby reduced. Other flushing embodiments are described in U.S. Pat. No. 4,319,929. Another improvement is described in U.S. Pat. No. 6,652,775 for solving the problem of cumulative pressure drops between SMB columns, which greatly prolong the washing process in cleaning the system. The '775 patent discloses washing means which, singly or simultaneously, wash defined units of one or more columns, utilizing the inlet feedstock and desorbent ports; and raffinate and extract outlet ports for ingress and egress of wash solution.
The key to achieving SMB process control, is the valve system which directs flows through the system, and regulates inputs and outputs. The early '589 patent employed a valve capable in any cycle step in the process, of directing feedstock or desorbent into a predetermined chamber, or matching an open inlet port to the conduit rising up to any predetermined chamber. The rest of the valve positions in the rotor were blind, so liquid was thereby forced to flow downward into the next vertical chamber. Amore recent valve device having vertical indexing is disclosed in U.S. Pat. No. 6,196,266. The valve assembly indexes horizontally with ports presented in the vertical cylindrical wall of the valve body. However, some patents describe valve systems arranged co-axially, and designed to turn vertically, as in U.S. Pat. No. 4,625,763. Instead of a rotary valve, many SMB systems have been devised that employ sets of individual valves. U.S. Parent No. 4,434,051 discloses three tiers of three way valves to control the four processes flows. Another U.S. Pat. No. 5,635,072 utilizes a set of three valves per chamber, configured so that a continuously operated circulation pump can be eliminated, thereby conserving liquid volume in small, pilot scale system. U.S. Pat. No. 6,544,413 discloses a plural valve device having elements controlling input or output flow to each column in the SMB series. It has the advantage of reducing volume of liquid in the system for very small scale SMB systems.
Valves having a horizontally disposed plane of movement between stator and rotator are essentially of two types, one type in which stator portion is uppermost, and the other in which the stator is bottommost. The stator lowermost configuration was evident especially in the earlier large industrial units in which the columns were much too large to be moved. The rotary valve alone for some of these units (for example, U.S. Pat. No. 3,040,777) occupied an area of 64 sq. feet and weighed over 10 tons. U.S. Pat. No. 6,719,001 is a recent patent. An example of stator elements mounted in upper fixed position is disclosed in U.S. Pat. No. 4,764,276.
A persistent problem in the operation of rotary valves in SMB application is leaks, usually because of a failure of seals in gaskets in the valve assembly. Such sealing elements are prone to wear because of the substantial pressure under which they operate. In the '276 patent just referred to, sealing engagement is provided by the combination of a sealing wear ring and a compressible ring. Force is applied by a hydraulically actuated piston to obtain sealing of the rotating head assembly and its housing.